DESCRIPTION (From the applicant's abstract): Neurons and glia, like other cells, have highly regulated mechanisms for ensuring that proteins, once synthesized, are correctly sorted, stored, inserted into membranes or released from the cell. When one or more of these mechanisms is faulty the cell is stressed and a disease may result. The two systems that will be studied are the intracellular transport and fate of a myelin protein, (PMP22), in Schwann cells and of neurotrophins in CNS neurons. Mutations in duplications or deletions in the PMP22 gene are the cause of peripheral neuropathies. Aberrant trafficking of neurotrophins may contribute to degeneration of CNS neurons. PMP22 is a homodimer that forms heterodimers with a mutant PMP22 found in the Trembler-J mouse, an animal model for Charcot-Marie-Tooth (CMT) disease. Whether heterodimer formation occurs with other PMP22 mutants and what are the consequences in terms of trafficking and insertion into myelin will be determined. What are mechanisms that divert mutant PMP22s from their normal pathways and where and how are these proteins degraded before or during myelination? The experiments on the trafficking of epitope tagged or untagged PMP22 will be analyzed in Schwann or COS cells in culture, in myelinating co-cultures and in Trembler-J nerves. The involvement of neurotrophins in CNS function suggests that they are released from neurons, at least in part by regulatable pathways. The sorting and secretion of epitope-tagged neurotrophins by constituivie or regulatable pathways will be examined in cortical, hippocampal and retinal ganglion neurons in culture using Adenovirus mediated gene transfer. The sorting and trafficking of neurotrophins will be followed in the hippocampal and entorhinal cortex and basal forebrain either in transgenic mice expressing epitope-tagged neurotrophins or in tissue from animals stereotactically injected with Adeno- or Adneoassociated virus encoding the neurotrophins. The effect of short or long term exposure of hippocampal and cortical neuron dendrites to BDNF in vivo will be determined. Finally, whether NT-3 can promote axonal survival in two animal models of demyelination will be determined. Overexpression of NT-3 in muscle will be achieved through mating of a transgenic myo-NT-3 with either a PMP22-deficient mouse or the or the Trembler-J mouse.